Atherosusceptible Shear Stress Activates Endoplasmic Reticulum Stress to Promote Endothelial Inflammation.

Atherosclerosis impacts arteries where disturbed blood flow renders the endothelium susceptible to inflammation. Cytokine activation of endothelial cells (EC) upregulates VCAM-1 receptors that target monocyte recruitment to atherosusceptible regions. Endoplasmic reticulum (ER) stress elicits EC dysregulation in metabolic syndrome. We hypothesized that ER plays a central role in mechanosensing of atherosusceptible shear stress (SS) by signaling enhanced inflammation. Aortic EC were stimulated with low-dose TNFα (0.3 ng/ml) in a microfluidic channel that produced a linear SS gradient over a 20mm field ranging from 0-16 dynes/cm2. High-resolution imaging of immunofluorescence along the monolayer provided a continuous spatial metric of EC orientation, markers of ER stress, VCAM-1 and ICAM-1 expression, and monocyte recruitment. VCAM-1 peaked at 2 dynes/cm2 and decreased to below static TNFα-stimulated levels at atheroprotective-SS of 12 dynes/cm2, whereas ICAM-1 rose to a maximum in parallel with SS. ER expansion and activation of the unfolded protein response also peaked at 2 dynes/cm2, where IRF-1-regulated VCAM-1 expression and monocyte recruitment also rose to a maximum. Silencing of PECAM-1 or key ER stress genes abrogated SS regulation of VCAM-1 transcription and monocyte recruitment. We report a novel role for ER stress in mechanoregulation at arterial regions of atherosusceptible-SS inflamed by low-dose TNFα

Oxylipins in triglyceride-rich lipoproteins of dyslipidemic subjects promote endothelial inflammation following a high fat meal.

Elevated triglyceride-rich lipoproteins (TGRL) in circulation is a risk factor for atherosclerosis. TGRL from subjects consuming a high saturated fat test meal elicited a variable inflammatory response in TNFα-stimulated endothelial cells (EC) that correlated strongly with the polyunsaturated fatty acid (PUFA) content. This study investigates how the relative abundance of oxygenated metabolites of PUFA, oxylipins, is altered in TGRL postprandially, and how these changes promote endothelial inflammation. Human aortic EC were stimulated with TNFα and treated with TGRL, isolated from subjects' plasma at fasting and 3.5 hrs postprandial to a test meal high in saturated fat. Endothelial VCAM-1 surface expression stimulated by TNFα provided a readout for atherogenic inflammation. Concentrations of esterified and non-esterified fatty acids and oxylipins in TGRL were quantified by mass spectrometry. Dyslipidemic subjects produced TGRL that increased endothelial VCAM-1 expression by ≥35%, and exhibited impaired fasting lipogenesis activity and a shift in soluble epoxide hydrolase and lipoxygenase activity. Pro-atherogenic TGRL were enriched in eicosapentaenoic acid metabolites and depleted in esterified C18-PUFA-derived diols. Abundance of these metabolites was strongly predictive of VCAM-1 expression. We conclude the altered metabolism in dyslipidemic subjects produces TGRL with a unique oxylipin signature that promotes a pro-atherogenic endothelial phenotype

Scaffolding Discourse in Asynchronous Learning Networks

Discourse, a form of collaborative learning, is fundamentally a communications process. This in-progress study adapts Clark and Brennan’s grounding in communications principles to investigate how to “scaffold” asynchronous discourse. Scaffolding is defined as providing support for the learner at his or her level until the support is no longer needed. This paper presents early results from an experimental study measuring learning effectiveness. In the experiment, content and process scaffolding are manipulated based on pedagogic principles. A major contribution of the study is building and testing a technologymediated, discourse-centered, teaching and learning model called the Asynchronous Learning Networks Cognitive Discourse Model (ALNCDM). As discourse is one of the most widely used online methods of teaching and learning, the results of the study are expected to add to the body of knowledge on how to structure asynchronous online discourse assignments for more effective student learning

High-capacity Li4Ti5O12-C thick ceramic electrodes manufactured by powder injection moulding

Lithium-ion batteries are the most efficient electrochemical energy storage devices. However, there is still room for improvement in terms of safety and energy density, presently limited by conventional tape-casting electrode processing. In this study, a blend of the anodic material Li$_{4}$Ti$_{5}$O$_{12}$ with 2 wt% carbon black has been processed through powder injection moulding (PIM) yielding, after subsequent debinding and sintering processes, to ultra-thick (>500 µm) ceramic binder-free electrodes. The mixture of Li$_{4}$Ti$_{5}$O$_{12}$ with the thermoplastic binder composed of polypropylene, paraffin wax, and stearic acid is investigated to identify a rheologically suitable feedstock for the PIM process. The resulting disk-type green parts contain 50 vol% of ceramic powder. After removing the binder with solvents and subsequent thermal treatment, the parts are sintered at 900 °C, aiming for a relatively high porosity, i.e., 25.7%. The resulting electrodes show very high areal and volumetric capacities up to 26.0 mA·h·cm−2 and 403 mA·h·cm−3 at C/24, respectively, in a half-cell against lithium metal

Development of Future EU District Heating and Cooling Network Solutions, Sharing Experiences and Fostering Collaborations

Heating and cooling consume half of the EU’s energy and much of it is wasted. The lion’s share of heating and cooling is still generated from fossil fuels, mainly natural gas, while only 18% is generated from renewable energy. In order to fulfil the EU’s climate and energy goals, the heating and cooling sector must therefore sharply reduce its energy consumption and cut its use of fossil fuels. To this end the European Commission adopted a heating and cooling strategy in February 2016 as part of the wider Energy Union Package. A number of activities and projects funded by the programmes of European Union are supporting this new EU heating and cooling strategy

Ground calcium carbonate as a low cost and biosafety excipient for solubility and dissolution improvement of praziquantel

Calcium carbonate is an abundant mineral with several advantages to be a successful carrier to improve oral bioavailability of poorly water-soluble drugs, such as praziquantel. Praziquantel is an antiparasitic drug classified in group II of the Biopharmaceutical Classification System hence characterized by high-permeability and low-solubility. Therefore, the dissolution rate is the limiting factor for the gastrointestinal absorption that contributes to the low bioavailability. Consequently, the therapeutic dose of the praziquantel must be high and big tablets and capsules are required, which are difficult to swallow, especially for pediatric and elderly patients. Mixtures of praziquantel and calcium carbonate using solid-solid physical mixtures and solid dispersions were prepared and characterized using several techniques (X-ray diffraction differential scanning calorimetry, thermogravimetric analysis, scanning electron microscopy, laser diffraction, Fourier transform infrared and Raman spectroscopies). Solubility of these formulations evidenced that the solubility of praziquantel-calcium carbonate interaction product increased in physiological media. In vitro dissolution tests showed that the interaction product increased the dissolution rate of the drug in acidic medium. Theoretical models were studied to understand this experimental behavior. Cytotoxicity and cell cycle studies were performed, showing that praziquantel-calcium carbonate physical mixture and interaction product were biocompatible with the HTC116 cells, because it did not produce a decrease in cell viability or alterations in the cell cycle

Management of imatinib-resistant CML patients

Imatinib has had marked impact on outcomes in chronic myelogenous leukemia (CML) patients for all stages of the disease and is endorsed by international treatment guidelines as the first line option. Although imatinib is highly effective and well tolerated, the development of resistance represents a clinical challenge. Since the most frequently identified mechanism of acquired imatinib resistance is bcr-abl kinase domain point mutations, periodic hematologic, cytogenetic, and molecular monitoring is critical throughout imatinib therapy. Once cytogenetic remission is achieved, residual disease can be monitored by bcr-abl transcript levels as assayed by reverse transcription polymerase chain reaction (RT-PCR). Detection of bcr-abl mutants prior to and during imatinib therapy can aid in risk stratification as well as in determining therapeutic strategies. Thus, mutation screening is indicated in patients lacking or losing hematologic response. Moreover, search for mutations should also be performed when a 3-log reduction of bcr-abl transcripts is not achieved or there is a reproducible increase of transcript levels. In patients harboring mutations which confer imatinib resistance, novel second line tyrosine kinase inhibitors have demonstrated encouraging efficacy with low toxicity. Only the T315I bcr-abl mutant has proved totally resistant to all clinically available bcr-abl inhibitors. Strategies to further increase the rates of complete molecular remissions represent the next frontier in the targeted therapy of CML patients

Assessment on the Use of High Capacity “Sn4_{4}P3_{3}”/NHC Composite Electrodes for Sodium-Ion Batteries with Ether and Carbonate Electrolytes

This work reports the facile synthesis of a Sn–P composite combined with nitrogen doped hard carbon (NHC) obtained by ball-milling and its use as electrode material for sodium ion batteries (SIBs). The “Sn$_{4}$P$_{3}$”/NHC electrode (with nominal composition “Sn$_{4}$P$_{3}$”:NHC = 75:25 wt%) when coupled with a diglyme-based electrolyte rather than the most commonly employed carbonate-based systems, exhibits a reversible capacity of 550 mAh g$_{electrode}$$^{−1}$ at 50 mA g$^{−1}$ and 440 mAh g$_{electrode}$$^{−1}$ over 500 cycles (83% capacity retention). Morphology and solid electrolyte interphase formation of cycled “Sn$_{4}$P$_{3}$”/NHC electrodes is studied via electron microscopy and X-ray photoelectron spectroscopy. The expansion of the electrode upon sodiation (300 mAh g$_{electrode}$$^{−1}$) is only about 12–14% as determined by in situ electrochemical dilatometry, giving a reasonable explanation for the excellent cycle life despite the conversion-type storage mechanism. In situ X-ray diffraction shows that the discharge product is Na$_{15}$Sn$_{4}$. The formation of mostly amorphous Na$_{3}$P is derived from the overall (electro)chemical reactions. Upon charge the formation of Sn is observed while amorphous P is derived, which are reversibly alloying with Na in the subsequent cycles. However, the formation of Sn$_{4}$P$_{3}$ can be certainly excluded

Predicting zinc binding at the proteome level

BACKGROUND: Metalloproteins are proteins capable of binding one or more metal ions, which may be required for their biological function, for regulation of their activities or for structural purposes. Metal-binding properties remain difficult to predict as well as to investigate experimentally at the whole-proteome level. Consequently, the current knowledge about metalloproteins is only partial. RESULTS: The present work reports on the development of a machine learning method for the prediction of the zinc-binding state of pairs of nearby amino-acids, using predictors based on support vector machines. The predictor was trained using chains containing zinc-binding sites and non-metalloproteins in order to provide positive and negative examples. Results based on strong non-redundancy tests prove that (1) zinc-binding residues can be predicted and (2) modelling the correlation between the binding state of nearby residues significantly improves performance. The trained predictor was then applied to the human proteome. The present results were in good agreement with the outcomes of previous, highly manually curated, efforts for the identification of human zinc-binding proteins. Some unprecedented zinc-binding sites could be identified, and were further validated through structural modelling. The software implementing the predictor is freely available at: CONCLUSION: The proposed approach constitutes a highly automated tool for the identification of metalloproteins, which provides results of comparable quality with respect to highly manually refined predictions. The ability to model correlations between pairwise residues allows it to obtain a significant improvement over standard 1D based approaches. In addition, the method permits the identification of unprecedented metal sites, providing important hints for the work of experimentalists